title: Long term human reconstitution and immune aging in NOD-Rag (-)-γ chain (-) mice.
abstract: Aging of the human immune system is characterized by a gradual loss of immune function and a skewing of hematopoiesis toward the myeloid lineage, a reduction in the lymphocytic lineage, and progressive increases in senescent memory T cells at the expense of naïve T cells. Both the innate and the adaptive branches of the immune system are affected, including neutrophils, macrophages, dendritic cells and lymphocytes. Mice, the most common research model, although inexpensive, do not necessarily reflect the human immune system in terms of its interaction with infectious agents of human origin or environmental factors. This study analyzed whether a human immune system contained within the NOD-Rag (-)-γ chain (-) mouse model could realistically be used to evaluate the development and therapy of aging-related diseases. To that end lightly irradiated NOD-Rag (-)-γ chain (-) mice were injected intra-hepatically on day 1 of life with purified cord blood-derived CD34(+) stem and progenitor cells. Multiple mice were constructed from each cord blood donor. Mice were analyzed quarterly for age-related changes in the hematopoietic and immune systems, and followed for periods up to 18-24 months post-transplant. Flow cytometric analyses were performed for hematopoietic and immune reconstitution. It was observed that NOD-Rag (-)-γ chain (-) mice could be "humanized" long-term using cord blood stem cells, and that some evidence of immune aging occurred during the life of the mice.
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ 85724, United States. Electronic address: davidh@email.arizona.edu.
authors.forename: David T
authors.initials: DT
authors.lastname: Harris
authors.affiliation: Department of Immunobiology, University of Arizona, Tucson, AZ 85724, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Badowski
mesh_terms: D000375:Aging / Q000276:immunology; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D002469:Cell Separation; D016922:Cellular Senescence / Q000276:immunology; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D007107:Immune System / Q000502:physiology*; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D023421:Models, Animal; D011828:Radiation Chimera
chemical_list: D018952:Antigens, CD34; D018398:Homeodomain Proteins; D053631:Interleukin Receptor Common gamma Subunit; C064658:RAG-1 protein
keywords: CB; CD34; Cord blood; HSC; NOD/RAG(−/−)/IL2Rγ(null); NRG; NRG mice; PMN; Stem cells; cord blood; hematopoietic stem cells; polymorphonuclear cells